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Anaplastic ependymomas in childhood ● B. T IMMERMANN et al.

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viously reported perioperative mortality rate of 17% (24, 40) was diminished to 0% in our study.

et al. (15), who studied exclusively anaplastic ependymo- mas, found that by increasing the dose to the primary site, the outcome was positively influenced. We were unable to analyze the dose–response relationship for survival, how- ever, because the majority of the children were treated with a very small dose range (42–55.8 Gy) to the primary site, similar to the treatment approach used in the study of Rousseau et al. (6), who also could not demonstrate a difference. Recent advances in radiotherapy techniques have as their aim improvements in the therapeutic ratio in childhood brain tumors by adding potentially more effective strategies that increase tumor control and limit radiation toxicity. For example, hyperfractionated radiotherapy has the potential of safely increasing the dose to the tumor while sparing late effects (54). Pilot studies of hyperfractionated radiotherapy in medulloblastomas have revealed excellent tumor control of up to 95% in such patients with acceptable acute toxicity (55, 56). A Children’s Cancer Group Phase I/II trial investigated the effectiveness of hyperfractionated radiotherapy in brainstem gliomas with total doses of 78 Gy (57); although the survival rate remained poor, the treatment modality was tolerated relatively well with a prolonged need for steroid treatment and intralesional necrosis the only drawbacks. Another advance in radiotherapy is fractionated stereotactic irradiation, which focuses the dose on the tumor while sparing surrounding normal tissue, thus allowing bet- ter local dose escalation. Local dose intensification by ra- diosurgery might be a valuable approach, although data for children with CNS malignancies are scant . Grabb et al. (58) evaluated the role of stereotactic radiosurgery in 25 children with inoperable brain tumors, of whom 7 had ependymo- mas. The results in these patients with ependymomas were discouraging, but the authors (58) proposed that the therapy might be more effective if administered as part of primary treatment. Loeffler et al. (59) performed radiosurgery in 2 patients with ependymomas, both of whom were in com- plete remission 13 and 5 months after therapy. CONCLUSIONS The multimodal regimen used in the present study, con- sisting of adjuvant combined irradiation and chemotherapy, is effective in the treatment of anaplastic ependymomas in childhood. The predominant site of failure is the region of the primary tumor. The only significant predictive factors for overall and progression-free survival are the extent of resection and the dissemination of tumor at presentation. Therefore, exact staging techniques, including MRI of the brain and spine and cytologic studies of the CSF, are indis- pensable. Irradiation of the tumor site is sufficient for the treatment of localized supratentorial tumors. Whether this procedure is also sufficient for infratentorial ependymomas requires further studies to reduce toxicity. The prognosis remains very poor for patients with residual disease. In addition, because of the high frequency of local recurrence, it might be appropriate to intensify local treatment by using, for example, hyperfractionated schedules or a stereotactic

Chemotherapy The effectiveness of adjuvant chemotherapy is difficult to assess in our study because all patients received either maintenance or sandwich chemotherapy. However, former trials have failed to show a survival advantage for chemo- therapy, including the SIOP (Societe´ Internationale Oncolo- gie Pediatrique) and the Children’s Cancer Study Group trials (7, 16, 24, 37, 41, 42), but many patients with low- grade ependymomas also were enrolled in these studies, which could influence the results. Ependymomas have been shown to respond to chemotherapy (43–46). In particular, Needle et al. (34) reported in 1997 a survival benefit for adjuvant chemotherapy consisting of carboplatin, vincris- tine, ifosfamide, and etoposide, though they also included hyperfractionated radiotherapy in their treatment strategy. Ku¨hl et al. (47) reported a combined partial and complete response of 55% for patients with anaplastic ependymomas in the HIT88/89 trial. However, the chemotherapy admin- istered in our study population, which consisted of different agents given in different schedules, did not alter the prog- nosis in our patients. Irradiation Since postoperative irradiation started to be used, the survival rate has improved from 20% to 60% (5, 6, 9, 16, 48, 49). There is now uniform agreement that craniospinal radiotherapy is indicated for anaplastic ependymomas (21, 50) and useful in preventing spinal seeding (51). However, because some authors have reported that spinal seeding occurs only in infratentorial ependymomas (36, 52), others have prescribed craniospinal irradiation only for dissemi- nated and infratentorial tumors. This was the strategy in our trial and was based on these experiences. According to our findings, irradiation of the tumor region was sufficient for localized supratentorial tumors, and the distribution of risk factors was equivalent in both groups. At present, many oncologic centers treat localized infratentorial tumors with limited-volume irradiation to reduce toxicity. The impact of this approach on the risk of spinal failure is unclear. How- ever, the low spinal relapse rate observed in our study does not support this strategy since irradiation of the neuraxis was an essential part of treatment. An additional consider- ation in interpreting the findings from previous studies is that many low-grade ependymomas and also many adults have been included in some of these series and only a few children with infratentorial anaplastic ependymomas treated with local fields were observed for more than 5 years. In our series, radiotherapy of the craniospinal region in disseminated disease could not prevent progression despite irradiation of the neuraxis, thereby suggesting a need to intensify treatment. Another irradiation parameter is the dose level. Retro- spective series indicate that doses greater than 45 Gy have to be delivered to the primary site (48, 49, 52, 53). Merchant